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Acknowledgment: The authors thank Rikke Ogawa, MLIS, and Christopher Stave, MLS, Information Services Librarians, Lane Medical Library, Stanford University, for their assistance with the literature searches. They also thank Arthur Weltman, PhD, University of Virginia, for his insight and expertise in growth hormone and exercise physiology. Ms. Ogawa, Mr. Stave, and Dr. Weltman did not receive compensation for their contributions.

Grant Support: In part or fully by the Agency for Healthcare Research and Quality (National Research Service Award, grant no. HS000028-19), the U.S. Department of Veteran Affairs, Stanford University Medical Center, Stanford University, Genentech (fellowship stipend), the National Science Foundation, and the Evidence-Based Medicine Center of Excellence of Pfizer.

Conclusion:Claims that growth hormone enhances physical performance are not supported by the scientific literature. Although the limited available evidence suggests that growth hormone increases lean body mass, it may not improve strength; in addition, it may worsen exercise capacity and increase adverse events. More research is needed to conclusively determine the effects of growth hormone on athletic performance.

The use of human growth hormone to improve athletic performance has recently received worldwide attention. This practice, often called sports doping, is banned by most professional sports leagues and associations, including the International Olympic Committee, Major League Baseball, and the National Football League (1–3). However, a wide range of athletes, including those from baseball (4–6), cycling (7–8), and track and field (5, 9), have been implicated in or have confessed to illicit growth hormone use. The Mitchell report (10) recently identified 89 Major League Baseball players who allegedly used performance-enhancing drugs, and some of these players have subsequently admitted to using growth hormone (11–12).

Part of the attraction of using growth hormone as a performance enhancer has been that its use is difficult to detect. The World Anti-Doping Agency, whose formation stemmed from the widely publicized doping scandal of the 1998 Tour de France (13), first used a blood test to detect exogenous growth hormone during the 2004 Olympic Games in Athens. However, according to the World Anti-Doping Agency, there have been no test-confirmed positive cases for growth hormone doping in professional or Olympic athletes (14), probably because of the limited availability and implementation of this test.

Although growth hormone is reportedly used to enhance athletic performance and has been called the “most anabolic substance known” (15), its efficacy for this purpose is not well established. Some have suggested that growth hormone is a “wonder drug” (16) that results in “ripped muscle” (17) and provides “stamina-increasing properties” (18). Exogenous growth hormone therapy in growth hormone–deficient adults (that is, those with growth hormone deficiency due to hypothalamic or pituitary defects) results in increased lean mass and decreased fat mass (19), and comparable body composition changes are seen in healthy elderly adults who receive growth hormone (20). Some experts, however, have suggested that the strength-enhancing properties of growth hormone among healthy adults have been exaggerated (15). Serious side effects, including diabetes, hepatitis, and acute renal failure, may occur in athletes using high-dose growth hormone (21). Furthermore, the use of growth hormone for athletic enhancement is not approved by the U.S. Food and Drug Administration, and the distribution of growth hormone for this purpose is illegal in the United States (22).

We performed a systematic review of randomized, controlled trials to determine the effects of growth hormone therapy on athletic performance in healthy, physically fit, young adults. Our primary aim was to evaluate the effects of growth hormone on body composition, strength, basal metabolism, and exercise capacity. In addition, we sought to synthesize the evidence on adverse events associated with growth hormone in the healthy young and assess the quality of the published literature.

Methods

Literature Searches

In consultation with 2 research librarians, we developed individual search strategies to identify potentially relevant studies from the MEDLINE, EMBASE, SPORTDiscus, and Cochrane Collaboration databases. We sought English-language reports indexed through 11 October 2007 with keywords including growth hormone and randomized controlled trial (Appendix Table 1). We searched bibliographies of retrieved articles for additional studies.

Study Selection

We sought randomized, controlled trials, including crossover trials, that compared growth hormone therapy with no growth hormone therapy. We included studies that 1) evaluated at least 5 participants, 2) enrolled only community-dwelling participants, 3) assessed participants with a mean or median age between 13 and 45 years, and 4) provided data on at least 1 clinical outcome of interest. We excluded studies that 1) focused solely on evaluating growth hormone secretagogues, 2) explicitly included patients with any comorbid medical condition, or 3) evaluated growth hormone as treatment for a specific illness (for example, adult growth hormone deficiency or fibromyalgia).

Data Abstraction

One author reviewed the titles and abstracts of articles identified through our search and retrieved potentially relevant studies. An endocrinologist and a physician with training in meta-analytic techniques separately reviewed the retrieved studies and abstracted data independently onto pretested abstraction forms. We resolved abstraction differences by repeated review and consensus. If a study did not present data necessary for analysis or mentioned results but did not present data, we requested additional data from study authors. If data were presented graphically, we used the graph-digitizing program DigitizeIt, version 1.5 (Share It, Braunschweig, Germany), to abstract data from the graph (23). If multiple studies presented findings from the same cohort, we used these data only once in our analysis.

Quantitative Data Synthesis

To describe key study characteristics, we computed mean values weighted by the number of participants in the trial. To evaluate the effects of growth hormone on body composition and strength, we computed a change score for each clinical outcome for both the treatment and control groups as the value of the outcome at trial end minus the value of the outcome at trial start. We used these change scores to calculate the weighted mean difference and standard mean difference (26) effect sizes. The weighted mean difference is reported in the same units as the clinical outcome of interest, thereby facilitating clinical interpretation. Because our outcomes were similar for both methods, we present only the outcomes from the weighted mean difference method. For studies that did not report the variance of an outcome at trial end minus the value at trial start, we calculated it as the sum of the trial-start and trial-end variances minus twice the covariance (20, 27). Because trial-start data were not available for most of the studies reporting basal metabolic outcomes, we compared trial-end results between treatment and control groups for these outcomes. We combined studies by using random-effects models (26–28) because of potential interstudy heterogeneity.

The considerable variability in exercise protocols used in the included studies reporting exercise capacity outcomes made pooling these results inappropriate. Instead, we provide a narrative, qualitative assessment of exercise capacity outcomes and report their associated published P values.

The variability in reporting adverse events among included studies also made a quantitative meta-analysis of these outcomes inappropriate. Instead, we calculated the proportions of adverse events among participants who received and did not receive growth hormone in studies that reported or evaluated for each adverse event.

We performed sensitivity analyses and assessed interstudy heterogeneity to evaluate the robustness of our results. We removed each study individually to evaluate that study's effect on the summary estimates. We assessed publication bias by constructing funnel plots and calculated the number of unpublished studies required to statistically significantly change our results (28). We assessed heterogeneity among study results for each of the summary effects by calculating the Q statistic (and associated P value) and I2 statistic (26, 28–30). We evaluated heterogeneity through predetermined subgroup analysis that stratified studies by duration of treatment. We performed analyses by using Stata software, version 9.1 (Stata, College Station, Texas); SPSS, version 15.0 (SPSS, Chicago); and Comprehensive Meta-Analysis, version 2 (Biostat, Englewood, New Jersey). We considered P values less than 0.05 (2-tailed) to indicate statistically significant differences.

Role of the Funding Source

The authors were supported in part or fully by the Agency for Healthcare Research and Quality, Santa Clara Valley Medical Center, the U.S. Department of Veteran Affairs, Stanford University Medical Center, Stanford University, Genentech, the National Science Foundation, and the Evidence-Based Medicine Center of Excellence of Pfizer. These funding sources had no role in the design and conduct of the study; the collection, management, analysis, and interpretation of the data; the preparation, review, or approval of the manuscript; or the decision to submit the manuscript for publication.

Study Characteristics

The included studies enrolled 440 participants. Of these, 303 received growth hormone treatment, representing 13.3 person-years of treatment (Table 1). Study sizes were generally small (mean number of participants at enrollment, 15), and dropout rates were low (98% of participants completed the study protocols).

Growth hormone dosing regimens varied considerably among the included studies (Table 1). The studies could be divided into 2 principal types: those that evaluated the physiologic effects of a single dose of growth hormone and those that assessed the effects of longer-term dosing regimens. Seven studies evaluated the use of a single dose of growth hormone. Of these, 3 studies provided growth hormone subcutaneously (35–36, 38) and 4 studies provided growth hormone intravenously (34, 37, 39–40). Twenty studies provided growth hormone for more than 1 day (mean treatment duration, 20 days [SD, 18]) (Table 1). All of these studies provided growth hormone subcutaneously. Only 3 studies evaluated growth hormone for longer than 30 days (44–47, 70), and no study evaluated its use for more than 3 months. The mean daily dose of growth hormone was 36 µg/kg (SD, 21) among the included studies.

Effect of growth hormone (GH) on body composition.

We used a random-effects model and a weighted mean difference effect size to compare GH-treated and non–GH-treated participants. The black diamond represents the summary effect size for the outcome of interest. Values greater than 0 indicate that results with GH treatment were higher than those without GH treatment. The studies are ordered by mean effect size. *Male. †Female. ‡High-dose group. §Low-dose group.

Effect of growth hormone (GH) on strength.

We used a random-effects model and a weighted mean difference effect size to compare GH-treated and non–GH-treated participants. The black diamond represents the summary effect size for the outcome of interest. Values greater than 0 indicate that results with GH treatment were higher than those without GH treatment. The studies are ordered by mean effect size. 1RM = 1 repetition maximum.

Effect of Growth Hormone on Exercise Capacity

Six studies measured exercise capacity outcomes (Appendix Table 2). Given the variability in exercise interventions, we present a narrative summary rather than pooling their exercise capacity results. In growth hormone–treated participants compared with those not treated with growth hormone, lactate levels during exercise trended higher in all 3 studies evaluating this outcome, although this finding was statistically significantly higher in only 2 studies (Table 4). Exercising levels of plasma free fatty acids and glycerol were significantly increased in growth hormone–treated participants in all studies that evaluated these outcomes, reflecting the lipolytic properties of growth hormone. However, the exercising respiratory exchange ratio or respiratory quotient was not significantly different (35, 38, 72–74, 54–55) in growth hormone–treated participants compared with that in those not treated with growth hormone. Exercising heart rate was significantly increased in 2 of 4 studies that evaluated this outcome (35, 38). Maximum inspiratory pressure (at rest) increased in growth hormone–treated participants compared with those not treated with growth hormone in 1 study (72–74). Groups did not differ in bicycling speed, exercising energy expenditure, and power output (1 study each) (38, 54–55). Similarly, VO2max was not significantly different between growth hormone–treated and non–growth hormone–treated groups (2 studies) (33, 48, 72–74).

Safety of Growth Hormone

Growth hormone–treated participants reported higher rates of adverse events than those not treated with growth hormone (Table 5). The former group reported more soft tissue edema and fatigue than the latter group (44% vs. 1% and 35% vs. 0%, respectively). Growth hormone–treated participants also experienced arthralgias and carpal tunnel syndrome more often than did those not treated with growth hormone.

Sensitivity Analyses

We recalculated summary effect sizes after removing each study per iteration. Removing the study by Wolthers and colleagues (66–68) resulted in a statistically significant increase in weight among growth hormone recipients. Removing 1 of 5 studies that evaluated fat mass (32–33, 44–46, 48, 70, 72–74) or 1 of 4 studies that evaluated resting heart rate (33, 48, 53, 69, 72–74) resulted in nonsignificant differences between participants who received and those who did not receive growth hormone. The results of other clinical outcomes were robust to this analysis.

We found little evidence for statistical heterogeneity among the included studies for body composition, strength outcomes, resting respiratory exchange ratio or respiratory quotient, and resting energy expenditure (Appendix Figures 1 to 3). However, the summary results for resting heart rate were statistically heterogeneous (P for Q statistic = 0.01; I2 = 55%) (Table 3). Part of this heterogeneity could be explained by duration of growth hormone treatment. When we recalculated the resting heart rate from studies that provided growth hormone for at least 14 days, we found no evidence for heterogeneity (P for Q statistic = 0.26; I2 = 22%). We found little evidence of publication bias through visual inspection of funnel plots.

Discussion

Growth hormone is reported to be extensively used for illicit enhancement of athletic performance (5, 8, 75), both for its anabolic and endurance effects. However, our review of the limited published literature suggests that although growth hormone may alter body composition, it has minimal effect on key athletic performance outcomes and may, in fact, be associated with worsened exercise capacity. Our conclusions are consistent with the findings reported in the recent Mitchell report on illegal drug use in Major League Baseball, which noted the lack of evidence supporting growth hormone use and enhancement of athletic performance (10).

Athletes, in particular bodybuilders, reportedly use growth hormone to increase strength and improve muscle definition (5, 17, 76). We found that although growth hormone significantly increased lean body mass and was associated with a near-significant trend toward decreased fat mass, it did not result in gains in biceps and quadriceps strength. How can increases in lean body mass not translate into strength improvements? Because methods for evaluation of lean body mass do not reliably distinguish lean solid tissue from fluid mass (77) and because the included studies evaluated only short-term changes, we suspect that much of the increase in lean body mass from growth hormone is due to fluid retention rather than muscle hypertrophy (77–79). A nonrandomized study in experienced weightlifters supports this view. Yarasheski and colleagues (80) provided high-dose growth hormone to college football players and weightlifters and found that it did not increase muscle protein synthesis or decrease protein breakdown, suggesting that an increase in muscle mass from growth hormone use in such athletes is unlikely.

We found that growth hormone did not improve and, in fact, may worsen exercise capacity. Exercising lactate levels were significantly higher in growth hormone–treated participants than in non–growth hormone–treated participants in 2 of 3 studies that evaluated this outcome. Increased exercising lactate levels are associated with decreased exercise stamina and physical exhaustion (81). In the double-blind study by Lange and colleagues (38), 2 of 7 cyclists could complete the exercise protocol after receiving placebo but not growth hormone; this finding was replicated on repeated testing in 1 cyclist. It is not clear how growth hormone treatment increases exercising lactate levels, but it may be associated with increased action of uncoupling proteins in mitochondria or selective inhibition of pyruvate dehydrogenase (38). In addition, elevated glycerol concentrations observed during the growth hormone trials could provide an alternate gluconeogenic precursor, thus increasing blood lactate levels by reducing lactate clearance by the liver. However, our exercise capacity results must be interpreted with caution because all 3 studies evaluated exercising lactate levels after only 1 dose of growth hormone, a dosing protocol unlikely to mirror real-world regimens. Nonetheless, this finding merits further research because it suggests that endurance athletes who use growth hormone may actually be harming their athletic performance.

One recent study (72–74) included in our analysis reported respiratory function improvements (including maximum inspiratory and expiratory pressures) in participants treated with growth hormone compared with those not treated with growth hormone, although VO2max was not reported to statistically significantly differ. Whether these findings translate into improved athletic performance is unclear. In healthy people at sea level, pulmonary function is typically not considered to be limiting to performance (82). Even during maximal exercise, participants could increase ventilation (82), suggesting an existing ventilatory reserve. Additional studies evaluating the effects of pulmonary function change on athletic performance are needed to evaluate these authors' findings.

While growth hormone therapy resulted in increased use of lipids for fuel during rest (as noted by a statistically significantly lower resting respiratory exchange ratio and respiratory quotient), this improvement did not seem to persist during exercise. Although growth hormone therapy resulted in higher exercising serum free fatty acid and glycerol levels, exercising respiratory exchange ratio and respiratory quotient levels were not reported to significantly differ in growth hormone–treated versus non–growth hormone–treated participants. Free fatty acid availability can affect free fatty acid uptake at rest and during low-intensity exercise, but exercise intensity remains the predominant determinant of substrate selection and can override other influences, especially at high rates of work output. As is the case after endurance training, a lower respiratory exchange ratio and respiratory quotient, signifying increased lipid rather than carbohydrate oxidation, are thought to contribute to improved exercise endurance due to glycogen preservation (83). The observation that respiratory exchange decrements with growth hormone did not persist during exercise suggests that short-term growth hormone treatment may not enhance endurance, at least through a mechanism of altered substrate selection. This conclusion cannot be considered definitive given the small number of included studies, but it suggests that additional research is needed to further delineate growth hormone's effects on endurance.

We found higher rates of adverse events in growth hormone–treated participants than in non–growth hormone–treated participants. Consistent with studies in growth hormone–deficient patients (84–85) and healthy elderly participants (20), we found higher proportions of soft tissue edema, joint pain, and carpal tunnel syndrome in participants receiving growth hormone, although variability in reporting adverse events precluded us from performing statistical analyses on these results. Adverse events related to fluid retention have been well described in growth hormone–treated patients (86–87) and are thought to be due to growth hormone's effect on fluid homeostasis. Of note, growth hormone–treated participants reported higher rates of fatigue, consistent with our finding that growth hormone may in fact worsen exercise capacity.

Our study reflects the limitations of the included studies. First, our review highlights the lack of published evidence about the physiologic effects of growth hormone among athletic young adults. Although we reviewed thousands of studies, only 8 studies assessed strength and exercise capacity for growth hormone treatment in a randomized manner. Thus, our analysis may not have detected small but clinically relevant differences in outcomes and adverse events. Because no studies evaluated growth hormone for longer than 3 months, there is no evidence with which to evaluate the long-term use of growth hormone for athletic enhancement. In addition, because only a small percentage of participants were women, there is almost no evidence with which to evaluate the effect of growth hormone in physically fit young women. Second, published data on real-world doping regimens are limited, and growth hormone dosing regimens used in research settings may be lower than or otherwise differ from those used by athletes who engage in sports doping. Saugy and colleagues (75) reported that athletes may be using growth hormone in dosages ranging from approximately 15 to 180 µg/kg per day (75), which may be higher than dosages used in most of our included studies. Whether a graded dose response exists for growth hormone is unclear (15), and future research should evaluate growth hormone regimens used in real-world settings. Finally, anecdotal reports of sports doping regimens suggest that growth hormone is not typically used as a single agent (5), but rather is often combined with other drugs, including androgenic steroids, insulin, and antiestrogens (76). Real-world sports doping regimens may have different benefits and risks from those noted in our analyses.

Claims regarding the performance-enhancing properties of growth hormone are premature and are not supported by our review of the literature. The limited published data evaluating the effects of growth hormone on athletic performance suggest that although growth hormone increases lean body mass in the short term, it does not seem to improve strength and may worsen exercise capacity. In addition, growth hormone use in healthy young persons is frequently associated with adverse events. More research, including an identification and evaluation of real-world growth hormone doping protocols, is warranted to definitively determine the effects of growth hormone on athletic performance.

Mitchell G. Office of the Commissioner of Baseball, Major League Baseball. Report to the Commissioner of Baseball of an independent investigation into the illegal use of steriods and other performance enhancing substances by players in Major League Baseball. 13 December 2007. Accessed athttp://files.mlb.com/mitchrpt.pdfon 9 March 2008.

Effect of growth hormone (GH) on body composition.

We used a random-effects model and a weighted mean difference effect size to compare GH-treated and non–GH-treated participants. The black diamond represents the summary effect size for the outcome of interest. Values greater than 0 indicate that results with GH treatment were higher than those without GH treatment. The studies are ordered by mean effect size. *Male. †Female. ‡High-dose group. §Low-dose group.

Effect of growth hormone (GH) on strength.

We used a random-effects model and a weighted mean difference effect size to compare GH-treated and non–GH-treated participants. The black diamond represents the summary effect size for the outcome of interest. Values greater than 0 indicate that results with GH treatment were higher than those without GH treatment. The studies are ordered by mean effect size. 1RM = 1 repetition maximum.

Mitchell G. Office of the Commissioner of Baseball, Major League Baseball. Report to the Commissioner of Baseball of an independent investigation into the illegal use of steriods and other performance enhancing substances by players in Major League Baseball. 13 December 2007. Accessed athttp://files.mlb.com/mitchrpt.pdfon 9 March 2008.

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